Ivabradine and the addition salts of it with pharmaceutical acceptable acid have highly valuable pharmacological and therapeutic effects, especially bradycardic effects, thus these compounds can be used not only for the treatment or prevention of various clinical symptoms of myocardial ischemia such as angina, myocardial infarction and the associated rhythm disorders, but also for the treatment or prevention of various diseases involving rhythm disorders, especially supraventricular rhythm disorder. In particular the Ivabradine hydrochloride applied by Servier has been approved to be listed in 27 Europe countries by the European medical review administration (EMEA) in November 2005 for the treatment of chronic stable angina pectoris of normal sinus rhythm which has contraindication or intolerance to the beta receptor blocking agent.
U.S. Pat. No. 5,296,482A, 1993 (EP534859A1) describes a synthetic route of Ivabradine in detail.
U.S. Pat. No. 4,737,495 discloses acid which can be used to form addition salts with Ivabradine, especially nontoxic and pharmaceutical acceptable inorganic acids or organic acids. These acids include inorganic acids, such as, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids, such as acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, oxalic acid, benzoic acid, methylsulfonic acid, hydroxylethyl sulfonic acid, benzene sulfonic acid, etc.
Patent CN1583341A, CN1827600A, CN1827599A, CN1827602A, CN1827601A, CN1948292A and CN1948293A disclose the method for the preparation of Ivabradine hydrochloride in α-form, β-form, βd-form, γ-form, γd-form, δ-form, δd-form and the application of their pharmaceutical composition respectively.
But the research result related to various crystal form of Ivabradine addition salts and Ivabradine hydrochloride disclosed in the patents mentioned above is unsatisfactory. Although the U.S. Pat. No. 4,737,495 discloses the scope of pharmaceutical acceptable inorganic or organic acids, which may be suitable for forming the salts, the inventors did not make further research. It is easy for the person skilled in the art to think of the inorganic or organic acids suitable for salinization, however it is valuable to make a further research and find Ivabradine addition salts with better performance. After extensive study, the present inventors have found that Ivabradine hydrochloride is not the best choice for medicinal Ivabradine additionsalts. Firstly, the methods disclosed in the patents above can not insure to obtain relative pure single crystal form satisfactorily. Ivabradine hydrochloride exists various different crystal structure. The crystal form obtained under various conditions disclosed in the patents above is essentially polycrystal or mixed crystal. Secondly, the stability of various crystals form of Ivabradine hydrochloride is unsatisfactory. The stability of alpha form is relatively good, but the preparation process introduce toluene and 1-methyl-2-pyrrolidone as crystallization solvent that the crystal purity is unsatisfactory and the 1-methyl-2-pyrrolidone is difficult to be removed which can not meet medicinal needs.
In view of the medicinal value of Ivabradine and its salts, it is necessary to find pharmaceutical acceptable Ivabradine salts with more superiority.